The overall objective of this research is to gain a better understanding of the structural requirements for dopamine (DA) receptor activity. The study is centered about the use of a unique non-nitrogen-containing set of DA agonists. Although most investigators have envisioned an uncharged nitrogen as an essential portion of molecular makeup of agonists and antagonists of DA receptors, we hypothesize that the major role of the nitrogen is to provide a cationic charge on the side chain of the DA molecule, which in turn can bind to an anionic site on the DA receptor. Our initial studies with sulfonium analogs of DA have shown them to possess significant dopaminergic activity. We would like to extend these studies by preparing new analogs and selecting the most interesting compounds for studies of behavioral and biochemical systems in order to obtain a better understanding of how they interact with the vaious DA receptor systems (presynaptic and postsynaptic, D1 and D2). The specific aim of these experiments is to synthesize and characterize a new series of sulfur-containing compounds in order to determine the structure that produces maximum dopaminergic activity, and in addition to determine from structural activity relationship studies how analogous the sulfur-containing derivatives of DA re to known DA agonists. The effectiveness of the sulfur analogs of DA will be studied on different animal models of DA receptor activity. These will include (1) studying their ability to displace the binding of 3H-DA and 3H-ADTN from crude membrane brain preparations; (2) studying whether these analogs can stimulate DA-sensitive adenylate cyclase activity; (3) studying their ability to inhibit the release of 3H-glutamate from striatal slices; (4) studying whether they can inhibit prolactin release from anterior pituitary cells; (5) studying whether they can stimulate presynaptic DA receptors; (6) studying whether their direct injection into the striatum and the nucleus accumbens can produce circling behavior and hyperactivity, respectively; (7) studying the effects of these analogs on the biochemistry of DA neurons. In all of these studies the effects of the sulfur analogs that we synthesize will be compared to DA.